Uses
LY-2584702 is a p70 S6 kinase inhibitor with anti-tumor activity.
Biological Activity
LY2584702 is an orally active, ATP-competitive, potent and selective ribosomal protein S6 kinase (p70 S6 kinase, p70S6K, S6K1) inhibitor (IC50 = 4 nM; selective over 83 other kinases and 45 cell surface markers). LY2584702 inhibits HCT116 cellular S6 phosphorylation (IC50 0.1-0.24 μM) and shows anti-tumor efficacy in U87MG glioblastoma and HCT116 colon carcinoma xenograft models in vivo (2.5 mg/kg bid. po.).
Synthesis
1. 4-(4-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (the target compound) was dissolved in 360 mL of acetone to form a homogeneous solution.
2. p-Toluenesulfonic acid monohydrate (10.25 g, 53.9 mmol, 1.2 eq.) dissolved in a 20:1 solution of water:acetone mixture (40 mL) was slowly added to the above solution at 20 °C. The addition process was controlled to be completed within 20 minutes.
3. The reaction mixture was heated to 55 °C and maintained at this temperature for 1 hour.
4. Upon completion of the reaction, the mixture was slowly cooled to 25°C over a period of 1 hour.
5. The precipitated solid product was collected by filtration and the filter cake was washed with 40 mL of water to remove impurities.
6. The resulting solid was dried under vacuum at 50 °C to afford 4-(4-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine p-toluenesulfonate (23.9 g, 86% yield) as a white solid.
in vivo
LY-2584702 demonstrates significant single-agent efficacy in both U87MG glioblastoma and HCT116 colon carcinoma xenograft models at two dose levels of 2.5 mg/kg twice daily (BID) and 12.5 mg/kg BID. LY-2584702 demonstrates statistically significant tumour growth reduction at TMED50 (threshold minimum effective dose 50%) (2.3 mg/kg) and TMED90 (10 mg/kg) in the HCT116 colon carcinoma xenograft model[1]. To examine the role of S6K in vivo, EOMA cells expressing shAkt3 are implanted in nu/nu mice, then treated for 14 days with LY-2584702 or Rapamycin. Analysis of tumors removed after 14 days shows that LY-2584702 inhibits S6 phosphorylation almost as effectively as Rapamycin. Loss of Akt3 increases tumor growth as compared with pLKO. LY-2584702 treatment alone does not significantly affect the growth of pLKO tumors. However, LY-2584702 significantly reduces the growth of tumors with shAkt3[2].
IC 50
p70S6K: 4 nM (IC
50)
References
[1] Patent: WO2008/140947, 2008, A1. Location in patent: Page/Page column 66
[2] Patent: WO2008/140947, 2008, A1. Location in patent: Page/Page column 66-68
